tbuckley/cabot-search huggingface dataset:
India and Pakistan emerge as early victims of extreme heat conditions due to climate injustice
Authors: Yogesh Jain, Rachna Jain
Journal: BMJ (2022)

Summer weather and extreme heat came unusually early to South Asia this year leading to the hottest March in the last 122 years.These extreme heat conditions, which typically affect northern, central, and western parts of India and Pakistan, have also extended to southern parts of India, where people and governments are not as well prepared. 1Ambient temperatures reached above 47C in India by the end of April and 49.5C in Pakistan in early May with land surface temperatures reaching an unprecedented 62C on 4 May in central India. 2 We are still only in the middle of the hot season and await further high temperatures with dread, especially the peak heat period of Nau-tappa (nine-days of heat) usually around 25 May to 3 June.Although maximum temperatures are likely to decline in June and July, the heat may be more dangerous as humidity will increase in the moisture laden monsoon season.
Computational Identification of Preneoplastic Cells Displaying High Stemness and Risk of Cancer Progression
Authors: Tianyuan Liu, Xuan Zhao, Yuan Lin, Qi Luo, Shaosen Zhang, Yiyi Xi, Yamei Chen, Lin Lin, Wenyi Fan, Jie Yang, Yuling Ma, Alok K. Maity, Yanyi Huang, Jianbin Wang, Jiang Chang, Dongxin Lin, Andrew E. Teschendorff, Chen Wu
Journal: Cancer Research (2022)

Abstract Evidence points toward the differentiation state of cells as a marker of cancer risk and progression. Measuring the differentiation state of single cells in a preneoplastic population could thus enable novel strategies for early detection and risk prediction. Recent maps of somatic mutagenesis in normal tissues from young healthy individuals have revealed cancer driver mutations, indicating that these do not correlate well with differentiation state and that other molecular events also contribute to cancer development. We hypothesized that the differentiation state of single cells can be measured by estimating the regulatory activity of the transcription factors (TF) that control differentiation within that cell lineage. To this end, we present a novel computational method called CancerStemID that estimates a stemness index of cells from single-cell RNA sequencing data. CancerStemID is validated in two human esophageal squamous cell carcinoma (ESCC) cohorts, demonstrating how it can identify undifferentiated preneoplastic cells whose transcriptomic state is overrepresented in invasive cancer. Spatial transcriptomics and whole-genome bisulfite sequencing demonstrated that differentiation activity of tissue-specific TFs was decreased in cancer cells compared with the basal cell-of-origin layer and established that differentiation state correlated with differential DNA methylation at the promoters of these TFs, independently of underlying NOTCH1 and TP53 mutations. The findings were replicated in a mouse model of ESCC development, and the broad applicability of CancerStemID to other cancer-types was demonstrated. In summary, these data support an epigenetic stem-cell model of oncogenesis and highlight a novel computational strategy to identify stem-like preneoplastic cells that undergo positive selection. Significance: This study develops a computational strategy to dissect the heterogeneity of differentiation states within a preneoplastic cell population, allowing identification of stem-like cells that may drive cancer progression.
Fractal Analysis of Dynamic Stress CT-Perfusion Imaging for Detection of Hemodynamically Relevant Coronary Artery Disease
Authors: Florian Michallek, Satoshi Nakamura, Tairo Kurita, Hideki Ota, Kensuke Nishimiya, Ryo Ogawa, Takehito Shizuka, Hitoshi Nakashima, Yining Wang, Tatsuro Ito, Hajime Sakuma, Marc Dewey, Kakuya Kitagawa
Journal: JACC. Cardiovascular imaging (2022)
British Association of Dermatologists guidelines for the management of adults with delusional infestation 2022
Authors: Alia Ahmed, Andrew G. Affleck, Janet Angus, Iyas Assalman, Susannah E. Baron, Anthony Bewley, Jonathan M.R. Goulding, Richard Jerrom, Peter Lepping, Helen Mortimer, Reena Shah, Ruth E. Taylor, Andrew R. Thompson, M. Firouz Mohd Mustapa, Lina Manounah, N.J. Levell, B. McDonald, S.L. Chua, A. Bardhan, G. Petrof, P. Laws, A. Daunton, H. Frow, I. Nasr, M. Hashme, L.S. Exton, A.M. Constantin, L. Manounah, M.F. Mohd Mustapa
Journal: British Journal of Dermatology (2022)

The overall objective of the guideline is to provide up-to-date, evidence-based recommendations for the management of delusional infestation (DI) in adults. Linked Comment: I. Coulson. Br J Dermatol 2022; 187:457.
Associations Between Medicaid Insurance, Biomarker Testing, and Outcomes in Patients With Advanced NSCLC
Authors: Cary P. Gross, Craig S. Meyer, Sarika Ogale, Matthew Kent, William B. Wong
Journal: Journal of the National Comprehensive Cancer Network (2022)

Evidence suggests that patients with Medicaid experience lower-quality cancer care than those with commercial insurance. Whether this trend persists in the era of personalized medicine is unclear. This study examined the associations between Medicaid (vs commercial) insurance and receipt of biomarker testing, targeted therapy, and overall survival in patients with advanced non-small cell lung cancer (aNSCLC).We conducted a retrospective study of patients who received an aNSCLC diagnosis from January 2011 to September 2019 using a nationwide US healthcare database. Eligible patients were aged 18 to 64 years with Medicaid or commercial insurance at diagnosis. Receipt of biomarker testing (ALK, EGFR, ROS1, BRAF, and PD-L1) was assessed. The likelihood of testing, biomarker-driven therapy (cancer immunotherapy or tyrosine kinase inhibitor treatment), and mortality were compared by insurance type using adjusted Cox regression.Our sample included 6,145 commercially insured and 865 Medicaid beneficiaries. Medicaid beneficiaries were more likely to be Black or African American (20% vs 9.3%; P <.001) and were less likely to have undergone biomarker testing (57% vs 71%; P <.001). In the adjusted analysis, Medicaid beneficiaries were less likely to have evidence of testing (hazard ratio [HR], 0.81; P <.001), any first-line treatment (HR, 0.72; P <.001), and first-line biomarker-driven therapy (HR, 0.70; P <.001). Medicaid beneficiaries with evidence of biomarker testing had a lower risk of death compared with those without evidence of biomarker testing (HR, 1.27 [95% CI, 1.06-1.52]; P =.010). Higher risk of death was observed in patients with Medicaid versus commercially insured patients (HR, 1.23; P <.001); this result remained unchanged after adjusting for biomarker testing (HR, 1.22; P < .001) but was partially ameliorated after adjustment for testing and treatment type (HR, 1.12; P =.010).Medicaid beneficiaries with aNSCLC were less likely to receive biomarker testing and biomarker-driven therapies, which may in part contribute to a higher observed risk of mortality compared with commercially insured patients.
Deficiency of the splicing factor RBM10 limits EGFR inhibitor response in EGFR-mutant lung cancer
Authors: Shigeki Nanjo, Wei Wu, Niki Karachaliou, Collin M. Blakely, Junji Suzuki, Yu-Ting Chou, Siraj M. Ali, D. Lucas Kerr, Victor R. Olivas, Jonathan Shue, Julia Rotow, Manasi K. Mayekar, Franziska Haderk, Nilanjana Chatterjee, Anatoly Urisman, Jia Chi Yeo, Anders J. Skanderup, Aaron C. Tan, Wai Leong Tam, Oscar Arrieta, Kazuyoshi Hosomichi, Akihiro Nishiyama, Seiji Yano, Yuriy Kirichok, Daniel S.W. Tan, Rafael Rosell, Ross A Okimoto, Trever G. Bivona
Journal: Journal of Clinical Investigation (2022)

Molecularly targeted cancer therapy has improved outcomes for patients with cancer with targetable oncoproteins, such as mutant EGFR in lung cancer. Yet, the long-term survival of these patients remains limited, because treatment responses are typically incomplete. One potential explanation for the lack of complete and durable responses is that oncogene-driven cancers with activating mutations of EGFR often harbor additional co-occurring genetic alterations. This hypothesis remains untested for most genetic alterations that co-occur with mutant EGFR. Here, we report the functional impact of inactivating genetic alterations of the mRNA splicing factor RNA-binding motif 10 (RBM10) that co-occur with mutant EGFR. RBM10 deficiency decreased EGFR inhibitor efficacy in patient-derived EGFR-mutant tumor models. RBM10 modulated mRNA alternative splicing of the mitochondrial apoptotic regulator Bcl-x to regulate tumor cell apoptosis during treatment. Genetic inactivation of RBM10 diminished EGFR inhibitor–mediated apoptosis by decreasing the ratio of (proapoptotic) Bcl-xS to (antiapoptotic) Bcl-xL isoforms of Bcl-x. RBM10 deficiency was a biomarker of poor response to EGFR inhibitor treatment in clinical samples. Coinhibition of Bcl-xL and mutant EGFR overcame the resistance induced by RBM10 deficiency. This study sheds light on the role of co-occurring genetic alterations and on the effect of splicing factor deficiency on the modulation of sensitivity to targeted kinase inhibitor cancer therapy.
Effect of AXS-05 (Dextromethorphan-Bupropion) in Major Depressive Disorder: A Randomized Double-Blind Controlled Trial
Authors: Herriot Tabuteau, Amanda Jones, Ashley Anderson, Mark Jacobson, Dan V. Iosifescu
Journal: American Journal of Psychiatry (2022)

Altered glutamatergic neurotransmission is implicated in the pathogenesis of major depressive disorder. AXS-05 (dextromethorphan-bupropion) is an oral NMDA receptor antagonist and sigma-1 receptor agonist, which utilizes inhibition of CYP2D6 to increase its bioavailability. This phase 2 trial assessed the efficacy and safety of dextromethorphan-bupropion in the treatment of major depressive disorder.This randomized, double-blind, multicenter, parallel-group trial evaluated dextromethorphan-bupropion versus the active comparator sustained-release bupropion in patients 18-65 years old with a diagnosis of major depressive disorder of moderate or greater severity. Patients were randomly assigned to receive either dextromethorphan-bupropion (45 mg/105 mg tablet) or bupropion (105 mg tablet), once daily for the first 3 days and twice daily thereafter, for a total of 6 weeks. The primary endpoint was overall treatment effect on Montgomery-Åsberg Depression Rating Scale (MADRS) score (average of the change from baseline for weeks 1-6), assessed in all randomized patients whose diagnosis and severity were confirmed by an independent assessor and who received at least one dose of study medication and had at least one postbaseline assessment.Of 97 patients randomized, 17 did not have a confirmed diagnosis and severity based on the independent assessment, resulting in 80 patients in the efficacy population (dextromethorphan-bupropion, N=43; bupropion, N=37). The mean change from baseline in MADRS score over weeks 1-6 (overall treatment effect) was significantly greater with dextromethorphan-bupropion than with bupropion (-13.7 points vs. -8.8 points; least-squares mean difference=-4.9; 95% CI=-3.1, -6.8). MADRS score change with dextromethorphan-bupropion was significantly greater than with bupropion at week 2 and every time point thereafter (week 6: -17.3 vs. -12.1 points; least-squares mean difference=-5.2, 95% CI=-1.1, -9.3). Remission rates were significantly greater with dextromethorphan-bupropion at week 2 and every time point thereafter (week 6: 46.5% vs. 16.2%; least-squares mean difference=30.3%, 95% CI=11.2, 49.4). Response rates (≥50% decrease in MADRS score from baseline) at week 6 were 60.5% with dextromethorphan-bupropion and 40.5% with bupropion (least-squares mean difference=19.9%, 95% CI=-1.6, 41). Most secondary outcomes favored dextromethorphan-bupropion. The most common adverse events with dextromethorphan-bupropion were dizziness, nausea, dry mouth, decreased appetite, and anxiety. Dextromethorphan-bupropion was not associated with psychotomimetic effects, weight gain, or sexual dysfunction.In patients with major depression, dextromethorphan-bupropion (AXS-05) significantly improved depressive symptoms compared with bupropion and was generally well tolerated.
Dorzagliatin in drug-naïve patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial
Authors: Dalong Zhu, Xiaoying Li, Jianhua Ma, Jiao’e Zeng, Shenglian Gan, Xiaolin Dong, Jing Yang, Xiaohong Lin, Hanqing Cai, Weihong Song, Xuefeng Li, Keqin Zhang, Qiu Zhang, Yibing Lu, Ruifang Bu, Huige Shao, Guixia Wang, Guoyue Yuan, Xingwu Ran, Lin Liao, Wenjuan Zhao, Ping Li, Li Sun, Lixin Shi, Zhaoshun Jiang, Yaoming Xue, Hongwei Jiang, Quanmin Li, Zongbao Li, Maoxiong Fu, Zerong Liang, Lian Guo, Ming Liu, Chun Xu, Wenhui Li, Xuefeng Yu, Guijun Qin, Zhou Yang, Benli Su, Longyi Zeng, Houfa Geng, Yongquan Shi, Yu Zhao, Yi Zhang, Wenying Yang, Li Chen
Journal: Nature Medicine (2022)
Single-nucleus chromatin accessibility profiling highlights regulatory mechanisms of coronary artery disease risk
Authors: Adam W. Turner, Shengen Shawn Hu, Jose Verdezoto Mosquera, Wei Feng Ma, Chani J. Hodonsky, Doris Wong, Gaëlle Auguste, Yipei Song, Katia Sol-Church, Emily Farber, Soumya Kundu, Anshul Kundaje, Nicolas G. Lopez, Lijiang Ma, Saikat Kumar B. Ghosh, Suna Onengut-Gumuscu, Euan A. Ashley, Thomas Quertermous, Aloke V. Finn, Nicholas J. Leeper, Jason C. Kovacic, Johan L. M. Björkegren, Chongzhi Zang, Clint L. Miller
Journal: Nature Genetics (2022)
Abstract PR008: Immunosuppressive niche engineering at the onset of human colorectal cancer
Authors: Chandler D. Gatenbee, Ann-Marie Baker, Ryan O. Schenck, Maximilian Strobl, Jeffrey West, Mark Robertson-Tessi, Trevor A. Graham, Alexander R.A. Anderson
Journal: Cancer Research (2022)

Abstract The evolutionary dynamics of tumor initiation remain undetermined, and the interplay between neoplastic cells and the immune system is hypothesized to be critical in transformation. Colorectal cancer (CRC) presents a unique opportunity to study the transition to malignancy as pre-cancers (adenomas) and early-stage cancers are frequently detected and surgically removed. Here, we demonstrate a key role for the immune response in tumor initiation by studying tumor-immune eco-evolutionary dynamics from pre-cancer to carcinoma using a computational model, ecological analysis of digital pathology data, and multi-region exome sequencing and neoantigen prediction in a total of 62 patient samples. Modelling indicates there are several potential routes to malignancy, each of which uniquely sculpts tumor ecology and intra-tumor antigenic heterogeneity (aITH). In patient samples, the immune microenvironment was characterized using the spatial distribution of 17 markers across registered whole-slide images, as well as patterns of intra-lesion aITH measured using multi-region exome sequencing and neoantigen prediction. The patient data were best described by a model where adenomas that become immunogenic early on do not progress to CRC because they are under immune control; progression therefore proceeds in adenomas with low immunogenicity. In these tumors, immune suppression is initially low, but gradually an immunosuppressive niche that is depleted in CD8+ cytotoxic T cells expands. There was little evidence for immune blockade (PD-L1 expression) in tumor initiation or progression. These results suggest that re-engineering the immunosuppressive niche may prove to be an effective immunotherapy in CRC. Citation Format: Chandler D. Gatenbee, Ann-Marie Baker, Ryan O. Schenck, Maximilian Strobl, Jeffrey West, Mark Robertson-Tessi, Trevor A. Graham, Alexander R.A. Anderson. Immunosuppressive niche engineering at the onset of human colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr PR008.
Multiphoton Phosphorescence Quenching Microscopy Reveals Kinetics of Tumor Oxygenation during Antiangiogenesis and Angiotensin Signaling Inhibition
Authors: John D. Martin, Ryan M. Lanning, Vikash P. Chauhan, Margaret R. Martin, Ahmed S. Mousa, Walid S. Kamoun, Hee-Sun Han, Hang Lee, Triantafyllos Stylianopoulos, Moungi G. Bawendi, Dan G. Duda, Edward B. Brown, Timothy P. Padera, Dai Fukumura, Rakesh K. Jain
Journal: Clinical Cancer Research (2022)

The abnormal function of tumor blood vessels causes tissue hypoxia, promoting disease progression and treatment resistance. Although tumor microenvironment normalization strategies can alleviate hypoxia globally, how local oxygen levels change is not known because of the inability to longitudinally assess vascular and interstitial oxygen in tumors with sufficient resolution. Understanding the spatial and temporal heterogeneity should help improve the outcome of various normalization strategies.We developed a multiphoton phosphorescence quenching microscopy system using a low-molecular-weight palladium porphyrin probe to measure perfused vessels, oxygen tension, and their spatial correlations in vivo in mouse skin, bone marrow, and four different tumor models. Further, we measured the temporal and spatial changes in oxygen and vessel perfusion in tumors in response to an anti-VEGFR2 antibody (DC101) and an angiotensin-receptor blocker (losartan).We found that vessel function was highly dependent on tumor type. Although some tumors had vessels with greater oxygen-carrying ability than those of normal skin, most tumors had inefficient vessels. Further, intervessel heterogeneity in tumors is associated with heterogeneous response to DC101 and losartan. Using both vascular and stromal normalizing agents, we show that spatial heterogeneity in oxygen levels persists, even with reductions in mean extravascular hypoxia.High-resolution spatial and temporal responses of tumor vessels to two agents known to improve vascular perfusion globally reveal spatially heterogeneous changes in vessel structure and function. These dynamic vascular changes should be considered in optimizing the dose and schedule of vascular and stromal normalizing strategies to improve the therapeutic outcome.
Physicians Spreading Misinformation on Social Media — Do Right and Wrong Answers Still Exist in Medicine?
Authors: Richard J. Baron, Yul D. Ejnes
Journal: New England Journal of Medicine (2022)

Interview with Dr. Richard Baron on the role of certifying boards in addressing the problem of false information on social media. (07:08)Download In light of widespread falsehoods about Covid-19 and its treatment and prevention, the American Board of Internal Medicine has informed doctors that disseminating misinformation is grounds for disciplinary sanctions.
Comparison of Hepatic Arterial Infusion Pump Chemotherapy vs Resection for Patients With Multifocal Intrahepatic Cholangiocarcinoma
Authors: Stijn Franssen, Kevin C. Soares, Joshua Samuel Jolissaint, Diamantis I. Tsilimigras, Stefan Buettner, Sorin Alexandrescu, Hugo Marques, Jorge Lamelas, Luca Aldrighetti, T. Clark Gamblin, Shishir K. Maithel, Carlo Pulitano, Georgios A. Margonis, Matthew J. Weiss, Todd W. Bauer, Feng Shen, George A. Poultsides, James Wallis Marsh, Andrea Cercek, Nancy Kemeny, T. Peter Kingham, Michael D’Angelica, Timothy M. Pawlik, William R. Jarnagin, Bas Groot Koerkamp
Journal: JAMA Surgery (2022)

Intrahepatic cholangiocarcinoma (iCCA) is often multifocal (ie, satellites or intrahepatic metastases) at presentation.
<i>TP53</i>‐altered chronic lymphocytic leukemia treated with firstline Bruton's tyrosine kinase inhibitor‐based therapy: A retrospective analysis
Authors: Hua‐Jay J. Cherng, Raamis Khwaja, Rashmi Kanagal‐Shamanna, Guilin Tang, Jan Burger, Philip Thompson, Alessandra Ferrajoli, Zeev Estrov, Koji Sasaki, Deepa Sampath, Xuemei Wang, Hagop Kantarjian, Michael Keating, William G. Wierda, Nitin Jain
Journal: American Journal of Hematology (2022)

Long-term follow up of prospective studies has shown that continuous Bruton's tyrosine kinase inhibitor (BTKi) therapy leads to durable remissions in previously untreated patients with TP53-altered chronic lymphocytic leukemia (CLL); however, it is unknown how variant allele frequency (VAF) of TP53 mutation (TP53-m) or percentage of cells with deletion of chromosome 17p [del(17p)] influences efficacy of firstline BTKi. We performed a retrospective analysis of 130 patients with CLL with baseline del(17p) and/or TP53-m treated with BTKi with or without the BCL2 inhibitor venetoclax (VEN) and with or without CD20 antibody in the firstline setting. A total of 104/130 (80%) patients had del(17p). TP53-m was noted in 89/110 (81%) patients tested; there were 101 unique TP53-m with an available VAF. The 4-year progression-free survival (PFS) and overall survival (OS) rates were 72.9% and 83.6%. No baseline characteristics including IGHV mutation status and number of TP53 alterations were associated with significant differences in PFS or OS, though a trend toward shorter PFS with increasing karyotypic complexity (hazard ratio 1.08, p = .066) was observed. Del(17p) was identified in <25% of cells in 26/104 (25%) of patients, and 28/101 (28%) of TP53-m were low-burden with a VAF of <10%; outcomes of these patients were similar to those with high-burden lesions. This study suggests that low-burden TP53 alterations should not be ignored when assessing genomic risk in CLL in the era of targeted therapy.
Claudin-12 Deficiency Inhibits Tumor Growth by Impairing Transendothelial Migration of Myeloid-Derived Suppressor Cells
Authors: Hong Cao, Chen Ni, Le Han, Ruoqi Wang, Rosel Blasig, Reiner Haseloff, Yue Qin, Jie Lan, Xiaohan Lou, Pan Ma, Xiaohan Yao, Linlin Wang, Fei Wang, Linyu Zhu, Ningjing Lei, Ingolf E. Blasig, Zhihai Qin
Journal: Cancer Research (2022)

Abstract Migration of myeloid-derived suppressor cells (MDSC) out of the circulation, across vascular walls, and into tumor is crucial for their immunosuppressive activity. A deeper understanding of critical junctional molecules and the regulatory mechanisms that mediate the extravasation of MDSCs could identify approaches to overcome cancer immunosuppression. In this study, we used mice deficient in tight junction protein Claudin-12 (Cldn12) compared with wild-type mice and found that loss of host Cldn12 inhibited the growth of transplanted tumors, reduced intratumoral accumulation of MDSCs, increased antitumor immune responses, and decreased tumor vascular density. Further studies revealed that Cldn12 expression on the cell surface of both MDSCs and endothelial cells (EC) is required for MDSCs transit across tumor vascular ECs. Importantly, expression of Cldn12 in MDSCs was modulated by GM-CSF in an AKT-dependent manner. Therefore, our results indicate that Cldn12 could serve as a promising target for restoring the antitumor response by interfering with MDSCs transendothelial migration. Significance: Claudin-12–mediated homotypic interactions are critical for migration of myeloid-derived suppressor cells across vascular walls into tumor tissue, providing a potential therapeutic approach to overcome cancer immunosuppression.